Method for treating hypercholesterolemia, hyperlipidemia, and atherosclerosis

ABSTRACT

A method for reducing mammalian serum total cholesterol, LDL cholesterol, apolipoprotein B and triglyceride levels, by ingesting a stabilized rice bran derivative selected from the group consisting of an enzyme treated stabilized rice bran, an insolubilized fraction and mixtures thereof, thereby reducing serum total cholesterol, LDL cholesterol, apolipoprotein B and triglyceride levels in said mammal.

RELATED APPLICATIONS

The present application claim benefit to Provisional U.S. patentapplication Ser. No. 60/057,870, filed Sep. 2, 1997, the teachings ofwhich are incorporated herein by reference. This application is acontinuation of Ser. No. 09/143,159 filed Aug. 28, 1998 now U.S. Pat.No. 6,126,943.

FIELD OF INVENTION

The present invention relates to methods for treatinghypercholesterolemia, hyperlipidemia, and atherosclerosis in mammals byingesting a stabilized rice bran derivative.

BACKGROUND OF THE INVENTION

Hypercholesterolemia is a condition with elevated levels of circulatingtotal cholesterol, LDL-cholesterol and VLDL-cholesterol as per theguidelines of the Expert Panel Report of the National CholesterolEducational Program (NCEP) of Detection, Evaluation of Treatment of highcholesterol in adults (see, Arch. Int. Med. (1988) 148, 36-39). Inparticular, high level of LDL and VLDL are positively associated withcoronary arteriosclerosis while the high levels of high densitylipoproteins (HDL) are negative risk factors. The role of LDL oxidationis gaining much attention in the literature. It is well documented thatLDL becomes oxidatively stressed under pathological conditions and is nolonger recognized by the LDL receptors. The oxidized LDL is taken up bymacrophages within the subendothelial space, leading to the formation offatty streaks which are the basis of most advanced lesions.

Hypercholesterolemia is implicated as a high risk factor ofcardiovascular disease (CVD), including arteriosclerosis,atherosclerosis and xanthomatosis in humans. Hypercholesterolemia isinfluenced by diet, heredity, environment, life style, diseases andstress, leading to heart attacks and strokes at an early age.

Hyperlipidemia is a condition where the blood lipid parameters areelevated. The lipids fractions in the circulating blood are, totalcholesterol (TC), low density lipoproteins (LDL), very low densitylipoproteins (VLDL) and triglycerides (TG). As per the American HeartAssociation guidelines, the safe levels are represented below. Activetreatment by diet modifications and drugs are necessary to reduce therisk of fatality when the levels go abnormal.

Total Cholesterol (TC) >240 mg/dL LDL-C >160 mg/dL - Apo(B) Atherogenicfactor HDL-C <35 mg/dL Lp(a) Atherogenic factor Triglycerides (TG) >150mg/dL

Hyperlipidemia results from diet, heredity, lifestyle, environment,familial diseases, or stress. The condition may be inherited or may besecondary to another disorder, such as Systemic Lupus Erythematosus(SLE), Hypothyroidism, Nephrotic Syndrome, Cushing's Syndrome, DiabetesMellitus, obesity, alcoholism, Corticosteroid Therapy or EstrogenTherapy.

Hyperlipidemia predisposes one to coronary heart disease, cancer andobesity. Hyperlipidemia is one of the high risk factors useful in theearly diagnosis of these life threatening diseases. To some extent,hyperlipidemia can be corrected by diet modifications and treatment withdrugs.

Atherosclerosis is a cardiovascular condition occurring as a result ofnarrowing down of the arterial walls. The narrowing is due to theformation of plaques (raised patches) or streaks in the inner lining ofthe arteries. These plaques consist of foam cells of low-densitylipoproteins, oxidized-LDL, decaying muscle cells, fibrous tissue,clumps of blood platelets, cholesterol, and sometimes calcium. They tendto form in regions of turbulent blood flow and are found most often inpeople with high concentrations of cholesterol in the bloodstream. Thenumber and thickness of plaques increase with age, causing loss of thesmooth lining of the blood vessels and encouraging the formation ofthrombi (blood clots). Sometimes fragments of thrombi break off and formemboli, which travel through the bloodstream and block smaller vessels.

The blood supply is restricted to the heart, eventually forming a bloodclot leading to death. The major causes of atherosclerosis arehypercholesterolemia and hyperlipidemia is high circulating cholesteroland high lipids like LDL-cholesterol and triglycerides in the blood.These lipids are deposited in the arterial walls, obstructing the bloodflow and forming atherosclerotic plaques leading to death.

Atherosclerosis is responsible for more deaths in the U.S. than anyother single condition. Atherosclerotic heart disease involving thecoronary arteries is the most common single cause of death, accountingfor one third of all deaths. Atherosclerotic interference with bloodsupply to the brain (causing stroke) is the third most common cause ofdeath after cancer. Atherosclerosis also causes a great deal of seriousillness by reducing the blood flow in other major arteries, such asthose to the kidneys, the legs and the intestines.

Medication is not a satisfactory treatment because much of the damage tothe artery walls has already been done. Anticoagulant drugs have beenused to try to minimize secondary clotting and embolus formation, buthave little or no effect on the progress of the disease. Vasodilatordrugs are used to provide symptom relief, but are of no curative value.

Surgical treatment is available for certain high-risk situations.Balloon angioplasty can open up narrowed vessels and promote an unprovedblood supply. The blood supply to the heart muscle can also be restoredthrough a vein graft bypass. Large atheromatous and calcified arterialobstructions can be removed by endarterectomy, and entire segments ofdiseased peripheral vessels can be replaced by woven plastic tubegrafts.

With regard to reduction of hypercholesterolemia, in some instances thiscan be achieved by modification of the diet and/or use of drugs therebyminimizing the risk of fatality of the disease. Reduction of serumcholesterol in humans has been achieved by consumption of dietary plantfiber and other effective components of foods. However, there remains aneed for a safe and effective treatment for the above conditions whichare often interrelated with minimal risk or side effects. As apreventive cure, diet plays a crucial role in bringing down the lipidparameters. In addition to diet and exercise, there is a need for asupplemental therapy, possibly to prevent these conditions and insurebetter health, particularly in people who are genetically predisposed tosuch conditions. The present invention fulfills these and other needs.

SUMMARY OF THE INVENTION

It has now been surprisingly found that stabilized rice bran derivativesreduce serum total cholesterol, LDL cholesterol, apolipoprotein B andtriglyceride levels in mammals. As such, the present invention providesa method for reducing mammalian serum total cholesterol, LDLcholesterol, apolipoprotein B and triglyceride levels, by ingesting astabilized rice bran derivative such as, enzyme treated stabilized ricebran, an insolubilized fraction and mixtures thereof, thereby reducingserum total cholesterol, LDL cholesterol, apolipoprotein B andtriglyceride levels. In one embodiment, the derivative is administeredin an amount of about 10 grams to about 100 grams per day total in atleast 2 doses.

In another aspect, the present invention provides a method forincreasing the HDL/LDL cholesterol ratio in mammalian serum, byingesting a stabilized rice bran derivative such as, an enzyme treatedstabilized rice bran derivative, an insolubilized fraction and mixturesthereof, thereby increasing the HDL/LDL ratio.

In still yet another aspect, the present invention provides a processfor making an enzyme treated stabilized rice bran derivative by mixingstabilized rice bran with an aqueous solution to form about a 15% toabout a 35% aqueous rice bran slurry; adding an enzyme to the aqueousrice bran slurry to convert starch to dextrin, thereby forming an enzymetreated slurry, and then drying the enzyme treated slurry to form anenzyme treated stabilized rice bran derivative.

DESCRIPTION OF THE PREFERRED EMBODIMENT

I. Glossary

As used herein the term “apolipoprotein B” or “apoprotein B” or “Apo B”refers to the protein component of the LDL cholesterol transportproteins. Cholesterol synthesized de novo is transported from the liverand intestine to peripheral tissues in the form of lipoproteins. Most ofthe apolipoprotein B is secreted into the circulatory system as VLDL.

As used herein the term “arteriosclerosis” is a degeneration of thewalls of the arteries due to the formation of foam cells and aorticstreaks which narrow the arteries. This limits blood circulation andpredisposes an individual to thrombosis.

As used herein the term “atherosclerosis” is a disease of the arteriesin which fatty plaques develop on the inner walls, with eventualobstruction of blood flow.

As used herein the term “cardiovascular disease” is a disease of theblood vessels of the circulation system caused by abnormally highconcentrations of lipids in the vessels.

As used herein the term “enzyme treated stabilized rice bran derivative”refers to an enzyme treated stabilized rice bran made by mixing astabilized rice bran with an aqueous solution in a 15% to about a 35%aqueous slurry w/w; adding an enzyme to the aqueous rice bran slurry toconvert starch to dextrin; and then directly drying the dextrin solutionto form an enzyme treated stabilized rice bran derivative. The enzymetreated stabilized rice bran comprises about 20% to about 30% totaldietary fiber.

As used herein the term “GRAS” means generally regarded as safe withrespect to food additives.

As used herein the term “hypercholesterolemia” is a condition withelevated levels of circulating total cholesterol, LDL-cholesterol andVLDL-cholesterol as per the guidelines of the Expert Panel Report of theNational Cholesterol Educational Program (NCEP) of Detection, Evaluationof Treatment of high cholesterol in adults (see, Arch. Int. Med. (1988)148, 36-39).

As used herein the term “hyperlipidemia” or “hyperlipemia” is acondition where the blood lipid parameters are elevated in the blood.This condition manifests an abnormally high concentration of fats. Thelipids fractions in the circulating blood are, total cholesterol, lowdensity lipoproteins, very low density lipoproteins and triglycerides.

As used herein the term “lipoprotein” such as VLDL, LDL and HDL, refersto a group of proteins found in the serum, plasma and lymph and areimportant for lipid transport. The chemical composition of eachlipoprotein differs in that the HDL has a higher proportion of proteinversus lipid, whereas the VLDL has a lower proportion of protein versuslipid.

As used herein the term “stabilized rice bran derivative insolubilizedfraction” refers to a fraction of stabilized rice bran during apartitioning process. Specifically, after the stabilized rice branaqueous slurry is enzymatically treated as discussed fully below, it isthen pumped into a centrifuge where the insoluble fraction precipitatesout of the aqueous solution. The insoluble fraction is collected andthen dried, and subsequently ground into a powder. This powder is theinsoluble portion. In a preferred embodiment, the constituent parts andtheir percentages are listed in Tables I and IV.

As used herein the term “stabilized rice bran derivative solubilizedfraction” refers to a fraction during a partitioning process.Specifically, after the stabilized rice bran aqueous slurry isenzymatically treated, it is then pumped into a centrifuge where theinsoluble fraction precipitates out of the aqueous solution. The aqueousmaterial is pumped to a dryer and then dried. This dried aqueous portionproduces the soluble fraction. In a preferred embodiment, theconstituent parts and their percentages are listed in Tables I and V.

As used herein the term “triglyceride” means a lipid or neutral fatconsisting of glycerol combined with three fatty acid molecules.

As used herein the term “xanthomatosis” is a disease evidence by ayellowish swelling or plaques in the skin resulting from deposits offat. The presence of xanthomas are usually accompanied by raised bloodcholesterol levels.

II. Detailed Description

In harvested rice, also known as rough rice, the kernel is completelyenveloped by the rice hull. The milling process removes the hull, whichyields brown rice. The outer brown layer is then removed by an abrasivemilling process to generate white rice. The separated brown layer isdesignated rice bran.

Rice bran is the mesocarp, i.e., the portion between the hull and ricegrain, obtained by milling or polishing brown rice. It constitutes about10% of rough rice. It is generally used as an animal feed. It containsabout 18-24% fat, about 25% dietary fiber, about 14% protein and about45% total carbohydrates besides several potent micronutrients. It isrich in B-complex vitamins, vitamin E and its isomers, minerals likepotassium, magnesium, and phosphorous besides several potentantioxidants.

Stabilized rice bran can be commercially purchased or prepared usingvarious methods. Most stabilization methods of rice bran result ininactivation of the lipases which are present, inactivation of theperoxidases, and inactivation of the microorganisms, while stillmaintaining the high levels of antioxidants in the rice bran. For ageneral discussion of stabilization and processing see; Rice Science andTechnology, edited by W. E. Marshall and James I Wadswoth, (1994) pages390-404.

Under normal conditions when brown rice is milled to rice, the oil inthe bran and the lipases also in the bran come into mutual contact,resulting in rapid degradation of the rice oil to free fatty acids andglycerol. The rice bran becomes unpalatable and is no longer suitablefor foodstuffs. However, if the lipases are inactivated, the rice branis thereby stabilized and the adverse effects on the bran are avoided.

There are many suitable means to stabilize or inactivate the lipase inrice bran, however most commercial systems utilize moisture-added or dryextrusion methods. These systems are selected because of theirrelatively low energy requirements, low capital costs and ease ofoperation. Stabilization by dry extrusion utilizes shear, friction, andpressure to generate the heat required to inactivate the lipase. Thetemperature of the bran must reach a temperature of a minimum of130°-140° C. for up to 3 seconds to assure inactivation of the lipase.

Acceptable extrusion stabilization can be achieved under less harshconditions by adding water or steam. The lipase is more heat sensitiveat higher moisture and can therefore be inactivated at somewhat lowerextrusion temperatures.

Residual peroxidase activity is generally used as the standard measureto make sure that lipase activity has been deactivated in stabilizedrice bran. Peroxidase is generally considered to be more heat stablethan lipase, and peroxidase activity assays are easier and more reliablethan the assays for lipase. The process conditions required toinactivate peroxidase as well as lipase can also cause modification toor loss of antioxidants in the bran. This can lead to fewer fatty acids,but the bran can be subject to oxidative rancidity. In addition, becausethe rice bran is susceptible to mold, yeast and bacteria, thestabilization process must effectively reduce the microbiological loadof the bran.

In addition to moisture added and extrusion techniques forstabilization, freezing and refrigeration of the rice bran result ineconomically viable processes to stabilize rice bran. Preferably,processes used to stabilize rice bran minimize the free fatty acidcontent, while maintaining high levels of antioxidants. Food gradestabilized rice bran is typically finely granulated, light tan in colorand possesses a relatively bland flavor with a nutty, toasted overtones.

Stabilized rice bran is available commercially from Producers Rice MillInc. (Stuttgart, Ark.), Riceland Foods (Stuttgart, Ark.) Riviana Foods,Inc. (Houston, Tex.), Uncle Ben's Inc. (Houston, Tex.) and TheRiceXCompany (El Dorado Hills, Calif.). Due to different stabilizationprocesses, stabilized rice bran will differ in composition andstabilization characteristics when derived from different manufacturers.

In order to generate the rice bran derivatives for use in the presentinvention, the rice bran is first stabilized, and then it is furtherseparated into at least two fractions. These include, but are notlimited to, a stabilized rice bran soluble derivative and a stabilizedrice bran insoluble derivative. Preferably, the separation into the ricebran derivatives includes a nonchemical process i.e., an enzymaticprocess. In this process, partitioning or fractionation preferablyproceeds as outlined hereinafter.

The stabilized rice bran is made into about a 15% to about 35% slurry,preferably, a 20-25% slurry with potable water. An enzyme, which caninclude, but is not limited to, a dextranase, a maltase, a α-amylase,and various other carbohydrate cleaving enzymes, is added to the batchconverting the starch to dextrins. The slurry is heated to about 150° F.to about 200° F. using for instance, a steam injection cooker, a heatexchanger or other heating method. The slurry is then pumped to ahorizontal centrifuge wherein the insoluble fraction is separated. Theinsoluble fraction is collected and then dried on a belt dryer, andsubsequently ground into a powder. This powder is the stabilized ricebran insoluble fraction. The aqueous material is pumped to a drum dryerand then dried. This dried aqueous portion produces the stabilized ricebran solubilized fraction.

The enzyme treated stabilized rice bran can be generated using the ricebran slurry as described above. As such, in another aspect, the presentinvention relates to the process for making an enzyme treated stabilizedrice bran derivative, comprising: admixing stabilized rice bran with anaqueous solution to form about a 15% to about a 35% aqueous rice branslurry, preferably a 20% to about a 30% aqueous rice bran slurry w/w;adding an enzyme to the aqueous rice bran slurry to convert starch todextrin, thereby forming an enzyme treated slurry and then directlydrying the enzyme treated slurry to form an enzyme treated stabilizedrice bran derivative.

In a preferred embodiment of the foregoing process, after the enzyme isadded to the slurry, the slurry is heated to about 100° F. to about 200°F. Preferably, the slurry is heated to about 150° F. to about 200° F.The slurry is then dried, wherein the drying is accomplished by aprocess such as belt drying, spray drying, drum drying and air drying.The drum drying process is preferred.

These stabilized rice bran derivatives are also available commerciallyfrom The RiceX Company of California. For the purpose of the invention,stabilized rice bran is available as RiceX™ Stabilized Rice Bran. Theinsoluble derivative is available as RiceX™ Fiber Complex and thesoluble derivative is available as RiceX Ricelin™ from The RiceXCompany, El Dorado Hills, Calif.

The stabilized rice bran derivatives can take a variety of forms. Theycan be a powder, a food, a food supplement, a medical food, a liquid, abeverage, an emulsion or mixture thereof. In addition, they can beincorporated into other edible materials. To incorporate the rice branderivative into the diet of a mammal various options include, but arenot limited to, simply sprinkling the derivative on another foodsubstance (i.e., salad, bread, cereal, etc.) being a major ingredient ina multigrain ready to eat cereal, incorporating it into a baked product(breads, muffins, waffles, etc), pasta, healthy dessert and snacks(athletic bar, healthy drink, etc.) and high fiber foods.

Stabilized rice bran contains about 18-23% fat, about 23-35% dietaryfiber, about 12-16% protein, about 8-36% total carbohydrate and manypotent microcomponents. Rice bran solubles contains about 15-40% fat,preferably 23-30% fat; about 0% to 25% dietary fiber, preferably about0-20% dietary fiber; about 0% to 15% protein, preferably 6-9% proteinand 25% to about 80% carbohydrates, preferably about 27-66% simplecarbohydrate and is a water soluble fraction. Stabilized rice braninsoluble derivative contains about 5%-20% fat, preferably 11-16% fat;about 40-65% dietary fiber, preferably 40-60% dietary fiber, and about10-30% protein, preferably 18-22% protein (see, Table I).

TABLE I COMPOSITION (est.) RiceX Stabilized Rice Bran Fat 18-23% Protein12-16% Total Dietary Fiber 23-35% Soluble Fiber 2-6% Carbohydrates 8-36% Ash  7-10% Moisture 4-8 RiceX Ricelin Fat 23-30% Protein 6-9%Total Dietary Fiber  0-20% Carbohydrates 27-66% Ash 3-7% Moisture 2-7%RiceX Fiber Complex Fat 11-16% Protein 18-22% Total Dietary Fiber 40-60%Soluble Fiber  0-12% Carbohydrates  0-12% Ash  8-12% Moisture 1-6%

With reference to Tables IV, V, VI and VII in Example 4, thesederivatives have been shown to have at least seventy-five (75) potentanti-oxidants. The major antioxidant vitamin E and its isomers known astocopherols (T) and tocotrienols (T₃) are collectively called tocols. Atocol rich substance is a mixture containing one or more compoundsselected from tocopherols (T), tocotrienols (T₃), and tocotrienol-like(T₃-like) compounds.

Antioxidant in stabilized rice bran derivatives include, but are notlimited to, γ-oryzanol, β-carotene, several known flavanoids,phytosterols, lipoic acid, and ferulic acid. Some of these compounds arepresent in high concentration, much more than in any of the knownnatural sources. It is believed that antioxidants particularly tocols,play a crucial role in significantly correcting certain metabolicdisorders singularly or synergistically as discussed below.

The stabilized rice bran soluble derivative is a powdered emulsion ofsoluble stabilized rice bran and germ, and is easily digested andabsorbed by the body. It can be taken by itself with a small amount ofwater to dissolve it in the mouth. It can also be mixed into liquidssuch as juice or hot drinks. Additionally, it is appropriate for use inbaked goods and other foodstuffs as discussed above. There are asignificant number of nutrients which have been discovered in rice bransolubles (stabilized rice bran solubilized derivatives).

The stabilized rice bran insoluble derivative binds bile acids therebylowering serum cholesterol levels, decreases triglyceride levels therebyhelping in the metabolism of cholesterol. It contains many highly potentantioxidants such as β-carotene, α, β, γ, and δ tocopherols andtocotrienols, phytate, oryzanols, glycosides and numerous phytosterolsand polyphenols. The rice bran insoluble derivative can also be mixedinto liquids such as juice or hot drinks. Additionally, it isappropriate for use in baked goods and other foodstuffs as discussedabove.

The enzyme treated stabilized rice bran derivative can also be mixedinto liquids such as juice or hot drinks. Additionally, it isappropriate for use in baked goods and other foodstuffs as discussedabove.

The present invention is based on the discovery that persons sufferingfrom hypercholesterolemia, hyperlipidemia, and atherosclerosis whoingest rice bran derivatives, such as the enzyme treated stabilized ricebran derivative, and stabilized rice bran insoluble derivative havesignificantly reduced serum total cholesterol, LDL cholesterol levels,apolipoprotein B and triglycerides. As such, the present inventionrelates to a method for reducing mammalian serum total cholesterol, LDLcholesterol, apolipoprotein B and triglyceride levels, the methodcomprises ingesting a stabilized rice bran derivative selected from thegroup consisting of an enzyme treated stabilized rice bran, aninsolubilized fraction and mixtures thereof, thereby reducing serumtotal cholesterol, LDL cholesterol, apolipoprotein B and triglyceridelevels in mammals. In a preferred embodiment, the mammal is a humanindividual.

It is presently preferred to administer the rice bran derivativesorally. In a preferred embodiment, the mammal ingesting the stabilizedrice bran derivative is suffering from any number of diseases, includingbut not limited to, hyperlipidemia, cardiovascular disease,atherosclerosis, arteriosclerosis and xanthomatosis.

The stabilized rice bran derivative is ingested in an amount of about 10grams to about 100 grams per day total, preferably in at least 2 doses.Preferably, the stabilized rice bran derivative is ingested in an amountof about 10 grams to about 40 grams per day total, and more preferably,in an amount of about 15 grams to about 30 grams per day total. Theoptimum dosage would be determined by the physician taking into accountthe age, weight and general health of the subject. The daily dosage canalso be administered in one or several treatments over a period of time,such as by way of single or multiple doses per day or from sustainedrelease compositions.

In another embodiment, the present invention relates to a method forincreasing the HDL/LDL cholesterol ratio in mammalian serum comprising:ingesting a stabilized rice bran derivative selected from the groupconsisting of an enzyme treated stabilized rice bran derivative, aninsolubilized fraction and mixtures thereof, thereby increasing saidHDL/LDL cholesterol ratio in the mammal.

Elevated levels of LDL and VLDL are positively associated with coronaryarteriosclerosis while the high levels of high density lipoproteins(HDL) are negative risk factors. Any dietary change which can decreasetotal cholesterol, LDL cholesterol levels will reduce risk ofcardiovascular disease, atherosclerosis, arteriosclerosis andxanthomatosis. Thus, in this aspect, ingesting a stabilized ricederivative in an amount of about 10 grams to about 100 grams per daytotal, preferably in at least 2 doses will reduce the HDL/LDL ratio.

The stabilized rice bran derivative can be ingested alone or, moreusually, in the form of a foodstuff comprising a therapeuticallyeffective amount of the stabilized rice bran derivative in combinationwith an inert GRAS food component and an acceptable diluent or carriertherefor.

The stabilized rice bran derivative can also be used in association withother therapeutic agents including, for example, antibiotics orantiviral agents.

The potent antioxidants in stabilized rice bran derivatives, namelyVitamin E and its isomers, in combination with the other antioxidantspresent in it, play a major role in treating atherosclerosis by reducingthe cholesterol levels, lipid levels, preventing platelet aggregation,preventing LDL-oxidation and restoring good blood supply to the heart.

The major antioxidants T and T₃ are thought to inhibit a key enzyme, HMGCoA reductase, in liver microsomes involved in the biosynthetic pathwayof cholesterol. The mechanism of T₃, in inhibiting HMG CoA reductaseinvolve post-transcriptional suppression of HMG CoA reductase in amanner mimicking the action of putative non-sterols feedback inhibitors.

Without being bound to a particular theory, it is believed that thebioactive components in rice bran derivatives, and their associatedmechanisms, positively effect the management of atherosclerosis,cardiovascular disease and the associated conditions ofhypercholesterolemia and hyperlipidemia. These bioactives seem to actsynergistically, creating an enhanced effect not expected when oneevaluates the individual compounds present in rice bran derivatives. Themajor bioactive components present in the rice bran derivatives aretocopherols, tocotrienols, γ-oryzanol, phytosterols, polyphenols,inositol, B vitamins, protein, fiber, and fat (see, Tables IV-VII). Someof the biological effects of these components and the mechanismsinvolved are set forth below.

1. Enzyme inhibitions: three enzymes, namely HMGCoA reductase, ACATtransferase and esterase are inhibited. HMGCoA reductase, a key enzymeinvolved in the cholesterol biosynthesis is inhibited by thetocotrienols, post transcriptionally, reducing the synthesis ofcholesterol resulting in low circulating cholesterol.

Acyl coenzyme A transferase (ACAT), inhibition is brought about byγ-oryzanol leading to:

a) the prevention of cellular cholesterol esterification therebyenriching high density lipoprotein cholesterol (HDL) with freecholesterol;

b) elevation of HDL, a positive effect, and decreased synthesis of verylow density lipoprotein cholesterol (VLDL); and

c) increased clearance of cholesterol as bile acids and bile salts.

The net result is lower circulating cholesterol. Cholesterol esterasesare inhibited by cycloartenol, a component of γ-oryzanol, resulting in aslower hydrolysis of cholesterol esters and decreased absorption. Thisresults in lower circulating total cholesterol.

2. γ-Oryzanol inhibits platelet aggregation, and aortic streaks thusreducing atherosclerosis.

3. Rice bran derivatives contain a significant variety and concentrationof antioxidants. Antioxidants such as tocopherols, tocotrienols,γ-oryzanol, polyphenols as ferulic acid, and lipoic acid are involved inthe repair of free radical damage, preventing low density lipoproteincholesterol (LDL) oxidation, resulting in the reduction of vasculardamage that can lead to cardiovascular disease.

4. Cycloartenol, a component of γ-oryzanol, has a structure similar tocholesterol and competes with receptor sites of cholesterol. This causesa sequestration of cholesterol as bile salts and bile pigments, thusmaintaining lower levels of circulating cholesterol.

5. Phytosterols and fiber facilitate cholesterol sequestration from thebody through increased excretion of bile salts and bile acids, resultingin lower levels of circulating cholesterol. The effect of soluble fiberin cholesterol management is well documented in the literature.

6. The protein, fat (with high levels of polyunsaturated andmonounsaturated fatty acids), and B vitamins also contribute to thehypocholesterolemic effect.

EXAMPLES Example 1

This example illustrates a clinical evaluation of stabilized rice branderivatives in a statistically significant population. Moreover theeffect of RiceX Stabilized Rice Bran, RiceX Ricelin (stabilized ricebran soluble derivative) and RiceX Fiber Complex (stabilized rice braninsoluble derivative) on blood glucose and lipid concentration in humansubjects. This clinical evaluation was carried out at the AdvancedMedical Research center at Madison, Wis. and at the Armed ForcesInstitute of Pathology, Rawalpindi, Pakistan.

Material and Methods

A. Product Description

RiceX Rice Bran, RiceX Ricelin and RiceX Fiber Complex are products richin fiber, non-starchy polysaccharides, complex carbohydrates, proteins,fats, B-complex vitamins, and potent antioxidants such, as β-carotene,vitamin E (Tocopherols and Tocotrienols), γ-oryzanol, phytosterols, andpolyphenols.

B. Product Codes

Product A: RiceX Stabilized Rice Bran;

Product B: RiceX Ricelin;

Product C: RiceX Fiber Complex

C. Subjects

Subjects selected were individuals with clinically established cases ofdiabetes mellitus (Type I or Type II), male or female, between the ageof 20-65 years, with ideal body weight (+20%), and no diagnosedcomplications. The subjects were under glycemic control with either oralhypoglycemic agents, or insulin therapy or both. All the subjects wereon National Cholesterol Education Program (NCEP) step-1 diet.

D. Dosage and Duration

The subjects were initially screened and randomly assigned to theRice_(x) product regimen. Test product was provided to each subject intwo equally divided doses of 10 grams each, one taken before breakfastand one taken before dinner in milk/fruit juice/water beverage. Thetotal dosage of 20 grams per day was provided to each subject every dayfor eight weeks.

E. Study Protocol

The products were given at random either in sequence, or individuallyfor eight weeks. When subjects were evaluated on more than one product awashout period of four weeks with a cellulose placebo to replacetreatment was used before switching to the next product. An initialfasting blood sample was drawn before each product regimen, and a finalfasting blood sample was drawn at the end of each product regimen. Theseblood samples were used for the measurement of glycemic and lipidparameters. Physical parameters such as body weight, body mass index,height, medications, and diet were measured and recorded for eachsubject. Blood glucose levels were monitored every morning beforebreakfast and every evening before dinner, by the subjects drawingcapillary blood and using a glucometer. Any significant change, likesudden hypoglycemic episodes were managed by reducing the medications aswell as the rice bran products on which the subjects were maintained, asrecommended by the study physician.

F. Biochemical Analysis

The initial and final blood samples of all the subjects before and afterthe treatment of each product were collected and stored at −80° C. untilanalyzed. These samples were analyzed for glycosylated hemoglobin,glucose, insulin, total cholesterol, LDL-Cholesterol, HDL-Cholesterol,Apo B, and triglycerides. All methods used were AOAC approved methods.

G. Statistical Analyses of the Data

All the parameters were statistically analyzed, using changes frombaseline values (0-time) to the end of study according to analyses ofvariance (Yanagava et al., Biometrics, 40:301-311, 1984.) These datawere compared among the three products.

Results

Table II summarizes the study of both Type I subjects on glycemic andlipidemic parameters, while Table III provides the data for the Type IIsubjects.

H. Type I Study

A total of 45 subjects with clinically established Type I diabetesmellitus were randomly treated with RiceX rice bran products either insequence or singularly as mentioned above. A total of 22 subjects weretreated with product A, 26 subjects with product B and 20 subjects withproduct C. The pooled averages of the data on glycemic and lipidparameters of the three products are given in Table II.

I. Type II Study

A total of 41 subjects with clinically established Type II diabetesmellitus were randomly treated with Rice_(x) Rice Bran products eithersingularly or in sequence as given in the protocol. A total of 23subjects were treated with product A, 31 subjects with product B and 26subjects with product C. The pooled averages of the data on glycemic andlipid parameters of all the three products are given in Table III.

J. Glycemic control

The results showed that there was a statistically significant (p=0.05)reduction in the glycosylated hemoglobin, by 11% when RiceX Ricelin wasprovided and by 10% when RiceX Fiber Complex was provided to the Type Isubjects for eight weeks. A similar statistically significant (p=0.05)reduction in glycosylated hemoglobin in Type II subjects was shown.RiceX Ricelin consumption for eight weeks led to a 10% reduction inglycosylated hemoglobin, while RiceX Fiber Complex consumption for eightweeks lead to an 11% reduction. Fasting serum glucose indicated astatistically significant (p<0.5) reduction of 33%, when compared to theinitial values, after eight weeks consumption of RiceX Ricelin in bothType I and Type II subjects. The RiceX Fiber Complex also showed adecrease in the fasting glucose levels of venous blood analysis of 19%and 22% in Type I and Type II respectively, when compared to initialtime values.

Type I subjects who consumed or RiceX Ricelin for eight weeks showed adecrease of 16% and 14% respectively for fasting glucose and glucosemeasured a ½ hour before dinner (monitored by glucometer). While RiceXFiber Complex consumption showed a decrease of 10% and 17% respectivelyfor serum fasting glucose and serum glucose measured a ½ hour beforedinner (monitored by glucometer).

In Type II subjects a decrease of 8% and 5% in fasting glucose andglucose ½ hr before dinner (monitored by glucometer) with RiceX Ricelinconsumption for eight weeks was observed. A 10% reduction in both theparameters with RiceX Fiber Complex was observed.

These data on glycemic parameters indicate that RiceX productssignificantly control and manage blood glucose levels in diabetesmellitus. More specifically, the reduction of glycosylated hemoglobinindicated that, in these subjects, consumption of RiceX Ricelin andRiceX Fiber Complex aided in increased control of blood glucose.

K. Lipid Parameters

Total cholesterol, LDL-Cholesterol, Apo B, and triglycerides of Type Isubjects who consumed RiceX Fiber Complex for eight weeks were reduced10%, 16%, 10%, and 7% respectively, when compared to zero-time values.There was no change in HDL-Cholesterol.

A greater reduction in lipid parameters was seen in Type II subjectsthan that noted in Type I subjects. Total cholesterol, LDL-Cholesterol,Apo B, and triglycerides were reduced by 12%, 15%, 10% and 8%respectively when compared to zero-time values. There was no change inHDL-Cholesterol concentrations after the consumption of RiceX FiberComplex. These results indicate that the RiceX Fiber Complexsignificantly controls hyperlipidemia.

TABLE II Results of Type I (IDDM) Subjects Product A (n = 22) Product B(n = 26) Product C (n = 20) Before After % Change Before After % ChangeBefore After % Change Glycemic parameters Phlebotomy Data GlycosylatedHb (%) 10.91 10.92 0 11.25 10.06 −11 11.32 10.23 −10 Fasting SerumGlucose 172.00 157.99 −9 174.16 116.97 −33 162.78 131.56 −19 (mg/dl)Serum insulin 49.36 49.71 0 52.75 54.86 4 52.03 51.99 0 (microunits/ml)Glucometer Data Fasting Glucose 159.45 154.95 −3 162.5 137.23 −16 164.95147.85 −10 (mg/dl) Glucose ½ hr. before 175.00 165.91 −5 168.12 145.35−14 175.35 144.95 −17 dinner (mg/dl) Lipid Parameters Serum TotalCholesterol 181.91 180.07 −1 174.27 166.14 −5 185.52 167.74 −10 (mg/dl)Serum LDL-Cholesterol 137.71 134.16 −3 130.79 122.35 −6 134.41 113.55−16 (mg/dl) Serum Apo B 88.15 86.15 −2 85.69 81.708 −5 84.37 75.96 −10(mg/dl) Serum Triglycerides 135.36 134.85 0 134.07 130.13 −3 129.76120.58 −7 (mg/dl) Serum HDL-Cholesterol 37.65 37.62 0 38.73 38.07 −239.29 39.57 0 (mg/dl)

TABLE III Results of Type II (NIDDM) Subjects Product A (n = 23) ProductB (n = 31) Product C (n = 26) Before After % Change Before After %Change Before After % Change Glycemic parameters Phlebotomy DataGlycosylated Hb (%) 10.22 10.63 4 10.69 9.65 −10 10.700 9.51 −11 FastingSerum Glucose 158.11 142.28 −10 158.18 106.52 −33 145.42 113.65 −22(mg/dl) Serum insulin 49.42 49.98 0 48.48 50.31 4 49.45 49.94 0(microunits/ml) Glucometer Data Fasting Glucose 120.13 121.71 1 128.45118.16 −8 129.12 115.73 −10 (mg/dl) Glucose ½ hr. before 120.17 129.91 8129.68 123.61 −5 134.54 120.96 −10 dinner (mg/dl) Lipid Parameters SerumTotal Cholesterol 182.81 172.79 −5 181.14 171.1 −6 186.04 164.58 −12(mg/dl) Serum LDL-Cholesterol 146.02 134.97 −8 143.18 131.48 −8 146.46124.77 −15 (mg/dl) Serum Apo B 95.56 94.23 −1 94.92 92.27 −3 95.00 85.62−10 (mg/dl) Serum Triglycerides 143.75 139.13 −3 138.85 135.47 −2 143.01131.24 −8 (mg/dl) Serum HDL-Cholesterol 36.23 36.21 0 34.42 34.33 033.64 33.54 0 (mg/dl)

Example 2

This example illustrates the synthesis of enzyme treated stabilized ricebran.

Twelve hundred pounds of stabilized rice bran was mixed with fivehundred seventy gallons of water to form a water extract. The mixturewas allowed to agitate for thirty minutes. Two hundred and forty gramsof α-amylase (Solvay Enzymes, Elkhart, Ind.) were added and allowed tomix for ten minutes. Thereafter the mixture was pumped through a heatexchanger set at about 190° F. and allowed to travel through a pipe coilfor 25 minutes. The mixture was then dried on a drum dryer to a moisturelevel below 5%.

Example 3

This example illustrates the synthesis of stabilized rice bran insolubleand soluble derivatives.

Twelve hundred pounds of stabilized rice bran was mixed with fivehundred seventy gallons of water to form a water extract. The mixturewas allowed to agitate for thirty minutes. Two hundred and forty gramsof α-amylase were added to the mixture and allowed to mix for tenminutes.

Thereafter the mixture was pumped through a heat exchanger set at about190° F. and allowed to travel through a pipe coil for 25 minutes. Themixture was then pumped to a horizontal decanting centrifuge set at3,600 RPM and fed at a rate of two gallons per minute. The solublefraction of the rice bran was separated from the insoluble fraction inthe centrifuge. The soluble fraction was then dried on a drum dryer to2.8% moisture. The insoluble fraction was also dried on a drum dryer to4% moisture. This process yielded 550 lbs. of dried rice bran insolublesand 420 lbs. of dried rice bran soluble concentrate. The chemicalcomposition of the two products are set forth in Tables IV and Vrespectfully.

Example 4

This example sets forth Tables IV-VII which tabulates components ofstabilized rice bran derivatives.

TABLE IV RiceX ™ FIBER COMPLEX MACRONUTRIENTS Protein 20.5% Fat 13.4%Total Dietary Fiber 49.5% (Soluble Fiber 0-1%) Carbohydrates  3.0% Ash10.0% Moisture  3.5% MICRONUTRIENTS Water Soluble Vitamins (mg/100Grams) Average Thiamine 2.00 Riboflavin 0.19 Niacin 30.55 PantothenicAcid 1.90 Vitamin B₆ 1.67 Biotin 0.011 Minerals (mg/100 Grams) AverageSodium 16.0 Calcium 92.5 Magnesium 1223.3 Potassium 1670.0 Vitamin E andOther “Tocol's” Average (mg/100 Grams) α-Tocopherol 0.74 τ-Tocopoherol0.40 δ-Tocopherol 0.43 Total Tocopherols 1.19 Tocopherols α-Tocopherol0.59 β-Carotene 1.55 τ-Tocopoherol 1.60 δ-Tocopherol 0.19 TotalTocopherols 2.54 Total TOCOLS 3.73 Vitamin A and Other CarotenoidsAverage (μg/100 Grams) α-Carotene TBD β-Carotene TBD Lycopene TBDPre-Lutein TBD Lutein TBD Zeaxantin TBD Pre-Cryptoxanthin TBDCryptoxanthin TBD β-Cryptoxanthin TBD Total CAROTENOIDS TBD τ-Oryzanol(mg/100 Grams) Average 174.1 Phytosterols (mg/100 Grams) AverageSitosterol 146.46 Brassicasterol 13.20 Campesterol 90.40 Stigmesterol67.15 Total PHYTOSTEROLS 317.2

TABLE V RiceX RICELIN ™ MACRONUTRIENTS Protein 7.5% Fat 26.5%  TotalDietary Fiber 3.0% Carbohydrates 54.5%  Ash 5.0% Moisture 3.0%MICRONUTRIENTS Water Soluble Vitamins Average (mg/100 Grams) Thiamine3.64 Riboflavin 0.46 Niacin 76.6 Pantothenic Acid 5.82 Vitamin B₆ 5.81Biotin 0.015 Minerals (mg/100 Grams) Average Sodium 15.75 Calcium 8.33Magnesium 170.8 Potassium 1562.0 Vitamin E and Other Average “Tocol's”(mg/100 Grams) α-Tocopherol 6.80 τ-Tocopoherol 1.13 δ-Tocopherol 0.07Total Tocopherols 8.00 α-Tocotrienol 4.90 β-Tocotrienol 0.36τ-Tocotrienol 4.48 δ-Tocotrienol 0.30 Total Tocotrienols 10.0 TotalTOCOLS 18.0 Vitamin A and Other Average Carotenoids (μg/100 g)α-Carotene TBD β-Carotene TBD Lycopene TBD Pre-Lutein TBD Lutein TBDZeaxantin TBD Pre-Cryptoxanthin TBD Cryptoxanthin TBD β-CryptoxanthinTBD Total CAROTENOIDS TBD τ-Oryzanol (mg/100 Grams) Average 248.1Phytosterols (mg/100 Grams) Average Sitosterol 211.90 Brassicasterol15.20 Campesterol 117.32 Stigmesterol 68.69 Total PHYTOSTEROLS 385.0

TABLE VI RiceX ™ STABILIZED RICE BRAN MACRONUTRIENTS Protein 14.5% Fat20.5% Total Dietary Fiber 29.0% (Soluble Fiber 2-6%) Carbohydrates 22.0%Ash  8.0% Moisture  6.0% MICRONUTRIENTS Water Soluble Vitamins Average(mg/100 Grams) Thiamine 2.65 Riboflavin 0.28 Niacin 46.87 PantothenicAcid 3.98 Vitamin B₆ 3.17 Biotin 0.014 Minerals (mg/100 Grams) AverageSodium 8.0 Calcium 39.7 Magnesium 727.0 Potassium 1573.0 Vitamin E andOther Average “Tocol's” (mg/100 Grams) α-Tocopherol 10.60 τ-Tocopoherol1.34 δ-Tocopherol 0.07 Total Tocopherols 11.97 α-Tocotrienol 7.56β-Tocotrienol 0.41 τ-Tocotrienol 5.36 δ-Tocotrienol 0.31 TotalTocotrienols 13.60 Total TOCOLS 25.61 Vitamin A and Other AverageCarotenoids (μg/100 Grams) α-Carotene 0.4 β-Carotene 37.0 Lycopene 2.3Pre-Lutein ND Lutein 63.8 Zeaxantin 18.4 Pre-Cryptoxanthin 7.4Cryptoxanthin ND β-Cryptoxanthin ND Total CAROTENOIDS 129.3 τ-Oryzanol(mg/100 Grams) Average 245.15 Phytosterols (mg/100 Grams) AverageSitosterol 151.47 Brassicasterol 14.61 Campesterol 91.57 Stigmesterol58.59 Total PHYTOSTEROLS 302

TABLE VII Antioxidants in RiceX ™ STABILIZED RICE BRAN A. τ-Oryzanol:(ppm) (2206-3000) Cycloartenyl Ferulate 24-Methylene CycloartanylFerulate Campesteryl Ferulate β-Sitosteryl Ferulate StigmasterylFerulate B. Tocopherols & Tocotrienols: (220-320 ppm) α-Tocopherolβ-Tocopherol τ-Tocopherol δ-Tocopherol α-Tocotrienol β-Tocotrienolτ-Tocotrienol Tocotrienols (Artifacts) C. Phytosterols: (2230-4400 ppm)4- Demethylsterols, 4-Methyl Sterol & Brassino Steriods β-SitosterolCampesterol Stigmasterol Δ5 Avinsterol Δ7 Stigmastenol Isofucosterolβ-Amyrin Gramisterol Citrostadienol Obtusifoliol Branosterol28-Homotyphasterol 28-Homosteasternoic Acid 6-Deoxycastasterone D. AminoAcids: (ppm) Tryptophan (2100) Histidine (3800) Methionine (2500)Cystine (336-448) Cysteine (3200) Arginine (10800) E. Polyphenols:α-Lipoic Acid Ferulic Acid Methyl Ferulate p-Coumaric Acid p-SinapicAcid F. Flavones and Proanthocyanidins Iso Vitexin Flavone GlycosidesOlegomeric Proanthocyanidins G. Other Antioxidants: (ppm) Inositol/MyoInositol (1200-1880) Phytic Acid/Phytates (1500--1710 Biotin (0.1-0.22)Choline (930-1150) H. Carotenoids: (0.9-1.6 ppm) α-carotene β-caroteneLycopene Lutein Zeasanthine I. Phospholipids: Phosphatidyl CholinePhosphatidyl Ethanolamine Lysolecithin J. Enzymes: GluthathionePeroxidase Methionine Reductase Super Oxide Dismutase Polyphenol OxidaseAspartate Amino Transferase Isoenzyme AAT-1 AAT-2 Coenzyme Q10 K.Polysaccharides: Cycloartenol Ferulic Acid Glycoside Diferulic AcidComplex Diferulic Acid + 3 Glucose + 2 Calcium ions complex L. MetalChelators: (ppm) Magnesium (6250-8440) Calcium (303-500) Phosphorous(14700-17000) M. B-Complex Vitamins: (ppm) Thiamine (22-31) Riboflavin(2.2-3.5) Niacin (370-660) Pantothenic Acid (36-50) Pyridoxine (29-42)

All publications, patents and patent applications mentioned in thisspecification are herein incorporated by reference into thespecification in their entirety for all purposes.

Although the invention has been described with reference to preferredembodiments and examples thereof, the scope of the present invention isnot limited only to those described embodiments. As will be apparent topersons skilled in the art, modifications and adaptations to theabove-described invention can be made without departing from the spiritand scope of the invention, which is defined and circumscribed by theappended claims.

What is claimed is:
 1. A method for controlling serum glucose in amammal, said method comprising: ingesting a therapeutically effectiveamount of a stabilized rice bran derivative selected from the groupconsisting of a stabilized rice bran derivative solubilized fraction, astabilized rice bran derivative insolubilized fraction, an enzymetreated stabilized rice bran and mixtures thereof, thereby reducingserum glucose in said mammal.
 2. The method in accordance with claim 1,wherein said mammal is a human.
 3. The method in accordance with claim1, wherein said mammal is suffering from diabetes mellitus.
 4. Themethod in accordance with claim 3, wherein said diabetes mellitus isType I.
 5. The method in accordance with claim 3, wherein said diabetesmellitus is Type II.
 6. The method in accordance with claim 1, whereinsaid rice bran derivative is a stabilized rice bran derivativesolubilized fraction.
 7. The method in accordance with claim 6, whereinsaid stabilized rice bran derivative solubilized fraction comprisesabout 0% to about 20% total dietary fiber w/w.
 8. The method inaccordance with claim 6, wherein said stabilized rice bran derivativesolubilized fraction comprises about 25% to about 80% total non-fibercarbohydrate content w/w.
 9. The method in accordance with claim 6,wherein said stabilized rice bran derivative solubilized fractioncomprises about 23% to about 30% total fat content w/w.
 10. The methodin accordance with claim 6, wherein said rice bran derivative is astabilized rice bran derivative solubilized fraction that comprisesabout 6% to about 9% total protein content w/w.
 11. The method inaccordance with claim 1, wherein said rice bran derivative is astabilized rice bran derivative insolubilized fraction.
 12. The methodin accordance with claim 11, wherein said rice bran derivative is astabilized rice bran derivative insolubilized fraction that comprisesabout 40% to about 60% total dietary fiber content w/w.
 13. The methodin accordance with claim 11, wherein said rice bran derivative is astabilized rice bran derivative insolubilized fraction that comprisesabout 1% to about 20% total non-fiber carbohydrate content w/w.
 14. Themethod in accordance with claim 11, wherein said rice bran derivative isa stabilized rice bran derivative insolubilized fraction that comprisesabout 10% to about 20% total fat content w/w.
 15. The method inaccordance with claim 11, wherein said rice bran derivative is astabilized rice bran derivative insolubilized fraction that comprisesabout 15% to about 25% total protein content w/w.
 16. The method inaccordance with claim 1, wherein said rice bran derivative is an enzymetreated stabilized rice bran.
 17. The method in accordance with claim16, wherein said enzyme treated stabilized rice bran comprises about 23%to about 35% total dietary fiber content w/w.
 18. A method for reducingglycosylated hemoglobin in a mammal, said method comprising: ingesting atherapeutically effective amount of a stabilized rice bran derivative,selected from the group consisting of a stabilized rice bran derivativesolubilized fraction, stabilized rice bran derivative insolubilizedfraction and mixtures thereof, thereby reducing glycosylated hemoglobinin said mammal.
 19. The method in accordance with claim 18, herein saidmammal is a human.
 20. A method for controlling serum glucose in amammal, said method comprising: ingesting a therapeutically effectiveamount of an enzyme treated stabilized rice bran.
 21. A method forimproving synthesis of insulin in a diabetic subject, said methodcomprising: ingesting a therapeutically effective amount of a stabilizedrice bran derivative solubilized fraction thereby improving synthesis ofinsulin in said mammal.
 22. The method in accordance with claim 21,wherein in said diabetic is a Type I diabetic.